4-Phenylethynyl benzylamines

ABSTRACT

This application discloses methods of preparing styrylaralkylamines and phenylethynylaralkylamines. The reaction of an N-formyl iodo benzylamine with a metal phenylacetylide followed by reduction or hydrolysis produces the desired phenylethynyl benzylamine. The corresponding strylaralkylamine is produced by a catalytic hydrogenation of the phenylethynyl benzylamine.

United States Patent 1 Remy 1451 *May6,1975

1 1 4-PHENYLETHYNYL BENZYLAMINES [75] Inventor: David C. Remy, North Wales. Pa.

[73] Assignee: Merck & Co., Inc.. Rahway, NJ.

1 Notice: The portion of the term of this patent subsequent to Mar. 6. 1990, has been disclaimed.

221 Filed: Jan. 7, 1972 121 App1.No.:216,264

Related 0.5. Application Data 1631 Continuation-in-part of Ser. No. 861,987, Sept. 29.

I969. Pat. No. 3,719,712v

[52] U.S. Cl. 260/293.72 [51] Int. Cl C07d 29/10 [58] Field of Search 260/5708, 570.9, 293.72.

[56} References Cited UNITED STATES PATENTS 3,719,712 3/1973 Remy 260/5709 OTHER PUBLICATIONS W. Theilheimer: Synthetic Methods of Organic Chemistry, 16: 219 (1962).

Gaylord; Reduction with Complex Metal Hydrides (1956), pages 551-553.

CA. 42: 4965 c (1948), Kon.

CA. 55: 1523 1526 (1961). Drefahl et a1,

Primary E.raminerHenry R. Jiles Assistant Examiner-S. D. Winters Attorney, Agent, or FirmDaniel T. Szura; Thomas E. Arther; Harry E. Westlake. Jr.

[57] ABSTRACT 5 Claims, No Drawings 4-PHENYLETHYNYL BENZYLAMINES This application is a continuation-in-part of Ser. No. 861,987 filed on Sept. 29, 1969, now US. Pat. No. 3,719,712.

This invention relates to unsaturated derivatives of aralkylamine compounds. More specifically, it relates to substituted and unsubstituted derivatives of styrylaralkylamines, phenylethynyl aralkylamines and the corresponding N-substituted derivatives such as the N- alkyl and N,N-dialkyl derivatives thereof.

This invention also relates to the novel processes and the novel intermediates utilized in the production of new aralkylamines, to pharmaceutical formulations of the new aralkylamines and to methods of treating or preventing cardiac arrhythmias using the novel compounds and/or pharmaceutical formulations thereof,

described hereinafter.

The new compounds of our invention are 1,2-diaryl derivatives of ethylene or acetylene whereinone of the aryl substituents is an aromatic ring having at least one of its hydrogens replaced by a straight or branched chain amino alkyl radical, or an amino heterocyclic radical, and in which the other substituent is a homocyclic or heterocyclic ring selected from aryl, substituted aryl, heterocyclic and substituted heterocyclic substituentsv The compounds of my invention are represented structurally as follows:

Al" C E C Arz in which Ar is a substituted or unsubstituted phenylalkylamine substituent and Ar is a substituted or unsubstituted aromatic ring.

A preferred class of compounds of our invention are represented structurally as aralkylamines of the forin which m is an integer varying from 1 to 4 inclusive and in which one or more of the methylene (CH hydrogens may be replaced by a lower alkyl substituent. R and R are either similar or dissimilar and are either hydrogen, alkyl (preferably of from 1 to 6 carbon atoms), branched chain alkyl, alkenyl, alkynyl (each preferably containing 1 to 6 carbon atoms), and can be joined together or alternatively may be linked through an atom of carbon, nitrogen, oxygen, or sulfur to one of the methylene substituents of the alkylene side chain to form a heterocyclic ring of l-morpholinyl, 4- thiomorpholinyl or l-loweralkyl-4-piperazinyl.

A preferred group of such compounds includes derivatives in which one or more of the hydrogens of the phenyl rings is replaced by substituents selected from the group consisting of hydrogen, or alkyl having up to 6 carbon atoms, an alkenyl group having up to 6 carbon atoms, a perfluoroalkyl group having up to 4 carbon atoms, a phenyl or a substituted phenyl radical, a dial kylamino group having up to 8 carbon atoms, an alkylsulfonylamino group having up to 4 carbon atoms, hydroxyl, an alkoxyl group having up to 4 carbon atoms, mercapto, an alkylmercapto group having up to 4 car bon atoms or a halogen such as fluoro or chloro.

An especially preferred group of compounds of the invention are represented by the following structural formula:

in which one or more of the hydrogens of the benzenoid rings may be replaced with fluoro, lower alkoxy of l-4 carbons, preferably methoxy, lower alkyl of from 1-4 carbons, preferably methyl, hydroxy, alkyl mercapto, alkyl sulfonyl, and trifluoromethyl, wherein R and R are hydrogen and the same or different lower alkyl substituents of from 1 to 4 carbons and R,, and R are lower alkyl substituents of from 1 to 3 carbon atoms.

Illustrative of the compounds included within the scope of the invention are a,a-dimethyl-4- (phenylethnyl) benzylamine, N,a,a-trimethyl-4- (phenylethynyl)benzylamine, N-methyl-cis or transa,a-dimethyl-4 styrylbenzylamine, 4-(phenylethynyl) benzylamine, 4-(4'methoxyphenylethynyl)benzylamine, 4-(4-tolylethynyl)benzylamine, 4-(4- fluorophenylethynyl)benzylamine, trans-4-styryl benzylamine, trans-4-(4-methoxystyryl)benzylamine, the N-lower alkyl and the N,N-dilower alkyl especially the N-methyl and the N,N-dimethyl derivatives thereof.

The compounds represented above, in either their free base or salt form, possess useful pharmacological properties. In particular, they have been found to possess antiarrhythmic activity. It has been found that the administration of compounds of the present invention, depicted in the above formula, results in the prevention of arrhythmia in animals under conditions which ordinarily cause the development of arrhythmia in the animal of the time.

It has further been found that administration of the compounds of the present invention will arrest an existing arrhythmia in the animal being treated and cause a resumption of normal cardiac rhythm. As antiarrhythmic agents, these compounds may be administered orally or parenterally. The formulations for administration may be prepared in conventional manner, employing conventional pharmaceutical carriers and excipients.

The non-toxic acid addition salts useful as components in the compositions provided by the present invention are salts formed by the reaction of an equivalent amount of the amine compound of the above formula and an acid which is pharmacologically acceptable in the intended doses. Salts of the above compound which are useful are salts of the amine with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, acetic acid, propionic acid, lactic acid, gluconic acid, maleic acid, succinic acid, tartaric acid and the like. Salts of these acids with the amine base are useful as the active component of the compositions in the method of this invention.

The daily doses are based on the total body weight of the test animal and vary between about 1.00 and 100.00 mg./kg. for mature animals. Thus, a unit dose based on four-times-a-day administration is between 2.5 mg. and 250 mg. for a 10 kg. dog, and a total daily dose for a 10 kg.' dog would vary between about 10 mg.

3 4 and l,000 mg. For larger animals, up'to 100 kg. and with a mixture of sodium cyanide and sulfuric acid in above, proportional dosages are employed, based on acetic acid as the solvent for a period of l to 12 hours, the weight of the animal. Suitable dosage units prothe product obtained is the intermediate N-formyl 4- vided for the administration of the compositions used d0-a.a-dialkyl benzylamine which is then mixed with in the method of the invention are tablets, capsules an q im l r m nt Ofa metal phenyl acetylide pref (which may be suitably formulated for either immcdierably cuprous phenyl acetylide of the formula:

ate or sustained release), syrups, elixirs, parenteral solutions and the like. These dosage forms preferably contain per unit one or more multiples of the desired dosage unit in combination with the pharmaceutically l0 acceptable diluent or carrier required for preparing the Q EC Cu dosage unit.

The compounds of my invention are prepared by a process outlined by the following structural formulas:

COOR R IE con LNHCHO 1 i l Grlgnaro R Rltter I R I I B C],

.c R c C R l 1*- g NHCHO (i-NHR wherein R is lower alkyl; R., is lower alkyl of from 1 to to form an N-formyl-a,a-dialkyl-4-(phenylethynyl)- 3 carbon atoms; R is lower alkyl of from 1 to 3 carbon benzylamine of the formula:

atoms; and R is H or CH In accordance with the process of the invention a 4' iodobenzoic acid ester of formula A hereinabove is treated under anhydrous conditions with a lower alkyl Grignard reagent, for example, methyl magnesium bro- R mide, and the product of the reaction hydrolyzed to 5 produce an a,a-dialkyl-4-iodo benzyl alcohol in which in which and R5 are lower alkyl f f to 3 the alkyl substituents are C -C straight chain saturated bong, aliphatic radicals, preferably methyl radicals. The product N-formyl-a,a-dialkyl-4-(4- h thynyllbenzylamine is then hydrolyzed by mixing with an aqueous solution of an organic or inorganic mineral acid or mixtures thereof. In the preferred instance an aqueous mixture of acetic and concentrated hydrochloric acid are employed and the reaction mixture is heated at the reflux temperature for about 2.5 hours.

In practice the hydrolysis reaction takes place at from 30-lO0C. for a period of from 1 to 24 hours.

The corresponding Nlower alkyl, e.g. the N-methyla,a-dialkyl-4-(4-phenylethynyl)benzylamine, is proln the instances in which R and R are different alkyl radicals, the starting material for the preparation of the tertiary alcohol is a 4-iod0-benzonitrile and the initial product obtained from the Grignard reaction and hydrolysis is a 4-iodophenylacetophenone. This ketone is then further reacted with an alkyl Grignard reagent followed by hydrolysis to produce the desired tertiary al coho] having R and R substituents which are different alkyl radicals.

This tertiary alcohol is then employed in a reaction d d by the r d ti n f the orre ponding N- which involves a reaction ofa tertiary carbinol B under lk l th N fo l -di lk l-4 (4 heny|e acid conditions. The starting material is mixed with hyh /b l i using an lk li t l r an alkali drogen cyanide in sulfuric acid preferably generated by t l l i h d id to produce th re lting N- a mixture of sodium cyanide in a solution of sulfuric lower alkyl, eg the N-methyl-a,adialkyl-4-(4 acid in acetic acid. The reaction was carried out for a phenylethynyl)benzylamine. period of from 15 minutes to ap roximately 24 hours, Preferably the reduction reaction is carried out using preferably for 6-10 hours, at 040C- wh n th C lithium aluminum hydride as the reducing agent and in P un m di kyl- -i n yl h is contacted a benzene solution. Other inert organic solvents such as ethers, e.g. tetrahydrofuran, diethyl ether, or other solvents usually employed with lithium aluminum hydride may be used.

The temperature is not critical and room temperature, i.e. C., is preferred but temperatures of from 0 to 50 are satisfactory. The produced N- alkylbenzylamine is preferably extracted and isolated as the hydrochloride salt.

The primary amines produced in accordance with my invention are readily converted to the corresponding N-alkyl or N,N-dialkylamines employing well-known reactions as illustrated in the following reaction flow sheet.

The corresponding N-(phenylethenylor phenylethnylbenzyl) formamide E in which R, is hydrogen is prepared by formylation of the benzylamine compound E employing conventional conditions and reagents such as formic acid or esters thereof for this purpose. The resulting formamide derivative can be recovered in conventional manner. The N,N-dimethylamine E wherein R and R each represent methyl, is readily prepared by the treatment of the primary amine compound E with formaldehyde and formic acid in accordance with the known Eschweiler-Clarke modification of the Leuckart Reaction. Recovery of the N,N- dimethylamine is accomplished in conventional manner. The N-methylbenzylamine, represented by E wherein Alk is methyl, may be prepared by either reduction of the corresponding N-(phenylethenylor phenylethynylbenzyl) formamide E or by monodealkylation of the corresponding N,N-dimethylamine E wherein R and R each represent methyl. Reduction of the formamide derivative is effected utilizing lithium aluminum hydride under the conditions set forth above. Similarly, dealkylation of the N,N- dimethylamine E can be effected in known manner such as by treatment with cyanogen bromide followed by hydrolysis of the intermediate cyanamide or by treatment with a haloformate followed by hydrolysis of the resulting urethane intermediate In each instance, the desired compound can be recovered employing conventional techniques.

The N-loweralkylamines and the N,N- diloweralkylamines corresponding to compounds E and E respectively, are likewise prepared from the corresponding primary amine E by analogous reactions. Thus, the primary amine E is treated with a lower aliphatic acid halide or anhydride of from 2-5 carbon atoms, e.g. acetyl chloride, acetic anhydride, propiony] chloride, butyryl chloride or valeryl chloride, to produce the N-alkanoyl amide corresponding to 5;, as, for example, the N-acetyl, N-propionyl, N-butyryl or N- valeryl amide. The thus-obtained amide is reduced to the corresponding N-loweralkyl benzylamine com pound E by reduction in the manner previously de scribed, i.e. by reduction with lithium aluminum hydride. The secondary amine compounds E produced in this manner are the N-loweralkyl derivatives of 4- (phenylethenyl or phenylethynyl)-a,a-dialkyl benzylamines as, for example, the N-ethyl, N-propyl, N-butyl and the N-amyl derivatives. The corresponding tertiary amines E the N,N-diloweralkyl derivatives, are prepared from the secondary amines by repeating the process employed in the preparation of the secondary amines. Thus, the amides of the secondary amines are prepared and reduced with lithium aluminum hydride to produce the corresponding tertiary amines as, for example, the corresponding N,N-diethyl, N-ethyl'N- methyl, N,N-dipropyl, N,N-dibutyl and the N,Ndiamyl derivatives of substituted and unsubstituted a,a-dialkyl phenylethenyl or phenylethynyl benzylamines.

In accordance with an alternative process for the preparation of the compounds of formula l5 wherein represents l-pyrrolidinyl, l-piperidyl, 4-morpholinyl, 4-thiomorpholinyl or 1-loweralkyl-4-piperazinyl, the primary amine E is condensed with an a,w-dihalo compound such as tetramethylene bromide, pentamethyl ene bromide, B,B-dichlorodiethyl ether, B,B-dichlorodiethyl sulfide, or an N-alkyl-B,B'-dichlorodiethyl amine.

In accordance with a further alternative process for the preparation of the primary, secondary and tertiary benzylamine products of my invention, a phenylethynyl or phenylethenyl halide of the formula shown below is converted by reaction with ammonia or an amine to produce the corresponding primary, secondary or tertiary amine as indicated below 2 \NH and R/ Hal-CH The starting compounds of the process of my invention, that is, the 4-iodo benzoic acid compounds and lower alkyl esters thereof. are either known compounds or may be readily prepared by simple procedures as for example by diazotization and replacement by iodine of the amino group in an appropriately substituted 4- amino benzoic acid.

The compounds of the invention which contain an ethenyl bridge can exist in two isomeric forms, the cis and trans isomers. These isomers have different physical characteristics and therefore are readily separable by conventional means as by crystallization.

Among the compounds prepared in accordance with the processes of the present invention are the a,a-dimethyl, a,a-diethyl, a,a-dipropyl, a-methyl-a-ethyl,

' a-methyl-a-propyl, a-ethyl-a-propyl, a-methyl-a-butyl benzylamines. The corresponding N-alkyl or N,N- dialkyl derivatives thereof, e.g. the N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N,N-diethyl, N,N-dipropyl, N-methyl-Nethyl, N-methyl-N-propyl, N-methyl-N- butyl and N-ethyi-N-propyl derivatives are prepared by methods described in the preceding pages for converting the benzylamine into the corresponding N-alkyl or N,N-dialkyl derivatives.

The corresponding ethylenic compounds, either cis or trans, of the formula and the corresponding N-alkyl and the N,N-dialkyl derivatives wherein R and R are hydrogen or lower alkyl are produced by selective hydrogenation of the corresponding acetylenic compound of the formula CEC dium, deposited on barium sulfate and treated with quinoline.

The cis and trans isomers are ordinarily separable by crystallization and exhibit different bioactivity.

EXAMPLE 1 a,a-Diemthyl-4-(phenylethynyl )-benzylamine hydrochloride A. Ethyl-4-iodobenzoate A solution of 100 grams (0.403 mole) of piodobenzoic acid in 600 ml. of abs. ethanol containing 30 ml. of concentrated sulfuric acid is refluxed for 5 days. The cooled solution is poured over 350 grams of ice and is neutralized with saturated sodium carbonate solution. The oil that separates is extracted with six I50 m1. portions of ether. These ether extracts are combined, washed with water, dried over magnesium sulfate, and filtered. Evaporation of the ether gives 131.3 grams of ethyl-4-iodobenzoate as a chromatographically pure, clear, light oil.

B. cur-Dimethyl-4-iodobenzyl alcohol A solution of 2.76 grams of ethyl-4-iodobenzoate in 10 ml. of ether is placed in a dry flask. The solution is cooled in an ice bath and is stirred. Over a 5 minute period, 26.5 ml. of a 1.52 M ethereal solution of methyl magnesium bromide is added. The solution is stirred for 3 hours while in the ice bath. Water (6 ml.) is added dropwise while stirring. The solution is filtered and the filter cake is washed with six 20 ml. portions of ether. The combined ether phases are dried over magnesium sulfate and filtered. Removal of the ether gives apt-dimethyl-4-iodobenzyl alcohol as a clear, light yellow liquid.

When the above experiment is repeated and ethyl-4- iodobenzoate is allowed to react with ethyl magnesium bromide or N-propyl magnesium bromide, the resulting compounds obtained are respectively a,a-diethyl-4- iodobenzyl alcohol or a,a-di(n-propyl)-4-iodobenzyl alcohol.

C. N-Formyl-a,a-dimethyl-4-iodobenzylamine Into a flask is placed l9 ml. of glacial acetic acid. The flask is cooled in an ice bath and the acetic acid forms a slush. Pulverized sodium cyanide (418 grams) is added over a 30 minute period while stirring. A precooled solution of 10.3 ml. of concentrated sulfuric acid in 9.5 ml. of glacial acetic acid is added to the stirred cyanide mixture over l5 minutes. The ice bath is removed, and 19.92 grams of a,a-dimethyl 4- iodobenzyl alcohol is added over 10 minutes. The white suspension is stirred minutes and is allowed to stand overnight at room temperature. The reaction mixture is poured over about 100 grams of ice, 100 ml. of water, and 100 ml. of ether. The mixture is neutralized with solid sodium carbonate. The aqueous phase is separated and extracted with two 100 m1. portions of ether. All of the ether phases are combined, washed three times with water, dried over magnesium sulfate, and filtered. Evaporation of the ether gives 18.17 grams of a reddish oil that crystallizes on standing. This solid is triturated with hot hexane and filtered to give N-formyl-a,mdimethyl-4-iodobenzylamine as a light grey solid. The product may be recrystallized from a benzenecyclohexane mixture to give white needles, m.p. 121l25C.

When the preceding experiment is repeated but utilizing in place of a,a-dimethyl-4-iodobenzyl alcohol ei ther a,a-diethyl-4-iodobenzyl alcohol or a,a-di(npropyl)-4-iodobenzylalcohol there is obtained the corresponding N-formyl-a,adiethyl-4-iodobenzylamine or N-formyl-a,a-di(n-propyl)4-iodobenzylamine.

D. NFormyl-a,a-dimethyl-4-(phenylethynyl)- benzylamine A solution of 1.0 gram of N-formyl-a,a-dimethyl-4- iodobenzylamine in 14 ml. of pyridine is placed in a flask. The solutioon is stirred under a N atmosphere. Cuprous phenylacetylide (0.57 gram) is added to this solution and the mixture is heated in an oil bath at 120C. At first, the mixture is a yellow suspension, but within 1.5 hours, a homogenous dark amber solution is obtained. The reaction is heated for hours at 120C. The cooled reaction mixture is poured onto 150 ml. of water and extracted with three 75 ml. portions of a 1:1 ether-benzene mixture. The extracts are combined, washed with two 50 ml. portions of dilute hydrochloric acid, two 50 ml. portions of 5% sodium hydroxide, two 100 ml. portions of water, and dried over magnesium sulfate. After filtration and evaporation of the solvent, there remains 0.78 gram of N-formyl-a,a-dimethyl-4- (phenylethynyl )-benzylamine as a clear oil that crystallizes on standing. The product may be recrystallized from isopropanol, m.p. l35-141C.

The experiment is repeated using in place of N- formyl-a,a-dimethyl-4-iodobenzylamine the corresponding N-formyl-a,a-diethyl-4-iodobenzylamine or N-formyl-a,a-di( n-propyl )-4iodobenzylamine with resultant production of N formyl-a,a-diethyl-4-(phenylethynyl)-benzylamine or N-formyl-a,a-di(n-propyl)-4- (phenylethynyl)-benzylamine.

E. a,a-Dimethy1-4-(phenylethynyl)-benzylamine hydrochloride A mixture of 0.50 gram of N-formyl-a,a-dimethyl-4- (phenylethynyl)-benzylamine, 10.7 ml. of glacial acetic acid, 6.7 ml. of water, and 1.07 ml. of concentrated hydrochloric acid is stirred and refluxed for 2.5 hours Starting Carbinol Phenylacetylide RER X The solution is evaporated to dryness and a,a-dimethyl-4-(phenylethynyl)-benzylamine hydrochloride is obtained as a light tan solid. The product is recrystallized from an isopropyl alcohol-methanoLether mixture to give pure a,a-dimethyl-4-(phenylethynyl )-benzylamine hydrochloride, m.p. 275-278 (decomp.).

Anal. Calcd. for C H N Cl:

Found; C, 74.18; H, 6.77; N, 5.30; CI, 13.11.

EXAMPLE 2 N,a,a-Trimethyl-4-( phenylethynyl )-benzylamine hydrochloride A solution of 2.92 grams of N-formyl-a,a-dimethyl- 4-(phenylethynyl)-benzylamine in 30 ml. of benzene is placed in a dry flask. The solution is stirred. A solution of 6.6 grams of a Red-Al solution in benzene is diluted with 30 ml. of benzene; this solution is added dropwise over approximately 30 minutes to the solution of N-formyl-oz,a-dimethyl-4-(phenylethynyl)- benzylamine. The reaction is hydrolyzed with water and is extracted thoroughly with a 1:1 benzene-ether solvent mixture. The combined extracts are dried over magnesium sulfate, filtered, and the solvent is evaporated to give 3.34 gm. of an oil. This oil is dissolved in ether and treated with ethanolic hydrogen chloride. The precipitate is collected and recrystallized from ispropanol to give N,a,a-trimethyl-4-(phenylethynyl)- benzylamine hydrochloride, m.p. 266268C.

Anal. Calcd. for C H NHCl:

Found: C, 75.72; H, 6.90; N, 4.76.

EXAMPLE 3 When Example 1 is repeated utilizing the starting materials indicated the respective indicated products are obtained:

Cuprous Product Amine lll R,&R X X R &R, X X methyl hydrogen 3-fluoro methyl hydrogen 3-fluoro 4-fluoro 4-fluoro Z-methoxy Z-methoxy 3-ethoxy 3-ethoxy 4-methoxy 4-methoxy Z-methyl Z-methyl 3-methyl 3-methyl 4-methyl 4-methyl 4-ethyl 4-ethyl Z-hydroxy 2-hydroxy 3-hydroxy B-hydroxy 4-hydroxy 4-hydroxy ethyl 3-fluoro ethyl 3-fluoro 4-fluoro 4-fluoro Z-methoxy 2-methoxy 3-cthoxy 3-ethoxy 4-methoxy 4methoxy Z-methyl Z-methyl 3-methyl 3-methyl 4-methyl 4'methyl 4-ethyl 4-ethyl 2-hydroxy Z-hydroxy 3-hydroxy 3-hydroxy 4'hydroxy 4-hydroxy methyl 3fluoro hydrogen methyl 3-l'luoro hydrogen 4-fluoro 4-fluoro 2-methoxy 2-methoxy 3-ethoxy 3-ethoxy 4-methoxy 4-methoxy 2-methyl Z-methyl 3-rnethyl 3-methyl d-methyl 4-methyl 4 ethyl 4-ethyl 2hydroxy 2-hydroxy 3-hydroxy 3-hydroxy 4hydroxy 4-hydroxy hydrogen 4-methylhydrogen 4-methyl sulfonyl sulfonyl 4methyl hydrogen 4-methyl mercapto rnercapto 4-trifluoro- 4-trifluoro methyl methyl EXAMPLE 4 lute ethanol. The white crystalline precipitate is col- 4-(Phenylethynyll-benzyl chloride Thionyl chloride, 7 ml., is added dropwise to a stirred solution of 6.0 g. (0.0288 mole) of 4-(phenylethynyl) benzyl alcohol in 100 ml. of dry chloroform at room temperature and the mixture is stirred for 6 hours. So]- vent is evaporated under reduced pressure and at a temperature below 50. The residue is freed from traces of thionyl chloride by dissolution in dry benzene and evaporation under reduced pressure. This process is repeated and the residual solid product is purified by sublimation in vacuo; m.p. 6l.563.5C.

Anal. Calcd for c,,n.,cr= c. 79.47; H, 4.89. Found: c, 79.60, 79.42; H, 4.98, 4.95.

EXAMPLE N-( 4-phenylethynylbenzyl)-piperidine 4 (Phenylethynyl)-benzyl chloride, 0.57 g. (2.5 mmole), is added to 5 ml. of piperidine and the mixture, from which a precipitate separates, is stirred for about 3 hours at room temperature. After evaporation of the bulk of the excess piperidine under reduced pressure, the residue is triturated with benzene and the insoluble piperidine hydrochloride removed by filtration. The benzene filtrate is washed with water and dried (MgSO Evaporation of the benzene under reduced pressure leaves 0.74 g. of the product as the residual oil. This oil is dissolved in isopropyl alcohol and treated with a slight excess of 7.2 N. hydrogen chloride in abso 5 phenylethynylbenzyl)piperidine hydrochloride, m.p.

Anal. Calc'd. for C H NHCl:

H, 7.1 l; N, 4.49.

Found: C, 77.25; H, 7.2l; N, 4.65.

EXAMPLE 6 N-Cyclopropyl-4-( phenylethynyl)-benzylamine A solution of 0.9 g. (4 mmole) of 4-(phenylethynyl)- benzyl chloride in 3 ml. of cyclopropylamine is heated to refluxing for 2 hours and then is allowed to stand at room temperature for several days. Another 1 ml. of cyclopropylamine is added and the solution is heated to refluxing for 4 hours. After evaporation of the excess cyclopropylamine, the residue is triturated with ether and the precipitate removed by filtration. The ethereal filtrate is evaporated and the residual oil dissolved in benzene. This solution is shaken with 10 ml. of 3N hydrochloric acid. The white crystalline hydrochloride salt of the product precipitates. It is collected and recrystallized twice from absolute methanol to give N- cyclopropyl-4-(phenylethynyl)-benzylamine hydrochloride, m.p. 2102l2C. dec.

Found: C, 76.35; H. 6.29; N, 4.95.

What is claimed is: thereof in which the alkyls contain from I to 4 carbons, l. A compound of the formula wherein R and R, are hydrogen or loweralkyl substituents.

2. a,a-Dimethyl-4-(phenylethynyl)benzylamine.

3. N,a,a-trimethyl-4-(phenylethynyl)-benzylamine. 4. N-(4-phenylenthynylbenzyl)-piperidine. 5. N-Cyclopropyl4(phenylethynyl)-benzylamine.

and N-loweralkyl and N,N-diloweralkyl derivatives 

1. A COMPOUND OF THE FORMULA
 2. Alpha , Alpha -Dimethyl-4-(phenylethynyl)benzylamine.
 3. N, Alpha , Alpha -trimethyl-4-(phenylethynyl)-benzylamine.
 4. N-(4-phenylenthynylbenzyl)-piperidine.
 5. N-Cyclopropyl-4-(phenylethynyl)-benzylamine. 